The long-term objective is to make CD8+ T cell-mediated immunity effective against fully established solid nonhemopoietic tumors, which represent the majority of human cancers. Experimentally, CD8 + T lymphocytes specific for tumor antigens are essential for effective immunity to most cancers. However, once cancers have grown for a week to several weeks, immunizations usually fail to affect tumor growth even though the mice are clearly immunologically responsive to the tumor antigens presented at a different site. Conceptually, the host develops in the tumor a physical and/or immunological "barrier" which may prevent access of CD8 + T cells to the tumor and inhibit continuing activation/proliferation of these T cells in the tumor and the development of memory. These mechanisms will be examined using TCR transgenic or normal T cells and mice carrying either transplanted tumor fragments in which the antigenic tumor cells are embedded in normal stroma or late established tumors in which the antigen is induced on the tumor cells by genetic recombination. Aim 1 determines the mechanism causing the impaired immune response to solid non-metastatic tumors; particularly how normal stroma affects antigen release and the localization, activation and memory formation of responding T cells. Aim 2 determines whether adoptively transferred CD8 + memory T lymphocytes can be made effective at the site of the established solid tumors by counteracting or neutralizing the local barrier. It will be determined whether antigens on growing tumors are sequestered from being accessed by memory T cells. In both of these Aims, it will be examined how the expression levels of cross-presented antigen, myeloid Gr-1 + FcR + barrier cells and IgG-TGF-beta can influence the induction and effector phase of CD8 + T cell immunity in the tumor-bearing host. Furthermore, the influence of CD4 + T cells in causing or counteracting the local barrier will be examined. Aim 3 tests whether findings in the first two aims are applicable to primary tumors caused by integrated E6/E7 sequences of HPV, and it will be determined whether (and under what conditions) E6/E7 specific CDS+T cells call prevent or eliminate these primary tumors. This will include testing a primary tumor model in which the timing, location and level of oncogene expression is controlled by topical induction. Together, studies should lead to a better understanding of how to make CD8 + T cell-mediated immunity effective against fully established solid tumors.